Patent GB-809820-A (GB)
Title: Improvements in or relating to steroids and the manufacture thereof
IPC: C07J75/00
Filed: 1956-11-09
Abstract: The invention comprises a 1-alkyl-9a -halo-11-oxygen-substituted-progesterone having the formula <FORM:0809820/IV (b)/1> in which R is (a - or b -) hydroxy or a keto group, X is halogen and the lower alkyl radical contains 1-8 carbon atoms and a process for the preparation of such a compound in which X is chlorine, bromine or iodine which comprises dehydrating a 2-alkyl-11b -hydroxy-progesterone to produce a 2-alkyl-4,9(11)-pregnadien-3,20-dione, reacting the latter compound with hypochlorous, hypobromous or hyporodous acid in an acid reaction medium and then if desired oxidizing the thus produced 2-alkyl 9a  - halo - 11b  - hydroxy - 4 - pregnene - 3,20-dione with chromic acid to produce the corresponding 2-alkyl-9a -halo-11-keto-progesterone. Compounds having the above formula in which X is chlorine or fluorine are obtained by reacting a 2 - alkyl - 9a  - halo - 11b  - hydroxy - 4-pregnen-3,20-dione prepared as above with a base e.g. anhydrous sodium acetate or aqueous sodium hydroxide, to produce a 2-alkyl-9b , 11b -epoxy - 4 - pregnene - 3,20 - dione and then reacting the latter compound with hydrogen fluoride or hydrogen chloride to produce a 2-alkyl 9a -fluoro- or chloro-11b -hydroxyprogesterone and then if desired oxidizing this compound to the corresponding 2-alkyl-9a -halo-11-ketoprogesterone with chromic acid.  The dehydration step may be effected with N-chloracetamide, N - bromoacetamide, N - chlorosuccimide, N - bromosuccinimide, N - iodosuccimide, N - bromophthalimide, 3 - bromo - 5,5-dimethyl hydantoin or 1,3-, 5,5-dimethyl hydantoin, in the presence of a basic compound, e.g. pyridine, picoline, lutidine, collidine, conyrine and parvaline. Formation of the halohydrin is effected with an N-haloamide or N-haloimide in the presence of a strong mineral acid, e.g. sulphuric acid or perchloric acid.  Conversion of the 9b ,11b -epoxy compound to the 9a -fluoro-compound is effected in an inert solvent in the presence of a boron trifluoride catalyst.  Examples disclose the preparation of 2 - methyl - 4,9(11) pregnadiene - 3,20 - dione, 2 - methyl - 9a  - bromo - 11b  - hydroxy - 4 - pregnen - 3,20 - dione, 2 - methyl - 9b ,11b  - epoxy-4 - pregnen - 3,20 - dione, 2 - methyl - 9a -fluoro - 11b  - hydroxyprogesterone, 2 - methyl-9a  - fluoro - 11 - keto progesterone and the corresponding 2-ethyl compounds.ALSO:2 - Alkyl - 9a  - halo - 11 - oxygen substituted progesterones having the formula <FORM:0809820/VI/1> in which R is a -hydroxy, b -hydroxy or a keto group, X is halogen and the lower alkyl radical contains 1-8 carbon atoms inclusive, are useful orally as in tablets, or topically as in ointments, lotions, jellies, creams and aqueous suspensions for the treatment of arthritic conditions and nervous system depressants. A dermatological and phthalmic ointment comprises wool fat, mineral oil, 2-methyl-9a -fluoro-11b -hydroxy-progesterone and white petrolatum.  An antibiotic such as neomycin sulphate may also be added.  In addition other antibiotics such as bacitracin, circulin, polymyxin B sulphate, gramicidin, streptomycin sulphate, dihydrostreptomycin sulphate, oxytetracyclin, chlortetracyclin, albamycin, tetracycline, chloramphenicol may be used to enhance the usefulness of the above ointments.